A visual and curatorial approach to clinical variant prioritization and disease gene discovery in genome-wide diagnostics

Background: Genome-wide data are increasingly important in the clinical evaluation of human disease. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. Recent work has shown that systematic integration of clinical phenotype data with genotype information can improve diagnostic workflows and prioritization of filtered rare variants. We have developed visually interactive, analytically transparent analysis software that leverages existing disease catalogs, such as the Online Mendelian Inheritance in Man database (OMIM) and the Human Phenotype Ontology (HPO), to integrate patient phenotype and variant data into ranked diagnostic alternatives. Methods: Our tool, “OMIM Explorer” (http://www.omimexplorer.com), extends the biomedical application of semantic similarity methods beyond those reported in previous studies. The tool also provides a simple interface for translating free-text clinical notes into HPO terms, enabling clinical providers and geneticists to contribute phenotypes to the diagnostic process. The visual approach uses semantic similarity with multidimensional scaling to collapse high-dimensional phenotype and genotype data from an individual into a graphical format that contextualizes the patient within a low-dimensional disease map. The map proposes a differential diagnosis and algorithmically suggests potential alternatives for phenotype queries—in essence, generating a computationally assisted differential diagnosis informed by the individual’s personal genome. Visual interactivity allows the user to filter and update variant rankings by interacting with intermediate results. The tool also implements an adaptive approach for disease gene discovery based on patient phenotypes. Results: We retrospectively analyzed pilot cohort data from the Baylor Miraca Genetics Laboratory, demonstrating performance of the tool and workflow in the re-analysis of clinical exomes. Our tool assigned to clinically reported variants a median rank of 2, placing causal variants in the top 1 % of filtered candidates across the 47 cohort cases with reported molecular diagnoses of exome variants in OMIM Morbidmap genes. Our tool outperformed Phen-Gen, eXtasy, PhenIX, PHIVE, and hiPHIVE in the prioritization of these clinically reported variants. Conclusions: Our integrative paradigm can improve efficiency and, potentially, the quality of genomic medicine by more effectively utilizing available phenotype information, catalog data, and genomic knowledge

Jaguar (Panthera onca) food habits in Atlantic rain forest of southeastern Brazil

Between January and December 1996, the food habits of a relict population of jaguars were studied in 220 km(2) Linhares Forest Preserve, which comprises much of the remaining old-growth Atlantic Forest of Espirito Santo, Brazil. Fecal analysis indicated opportunistic feeding on 24 prey species (N = 101 scats). Mammals represented 87 percent of the total items, followed by reptiles (9.8%) and birds (2.8%). Considering prey weight, 23.4 percent of the items weighed 1-3 kg, 40.5 percent were 3-10 kg, and 27.7 percent weighed more than 10 kg. Analysis of relative prey frequency and biomass indicated that the diet was concentrated in two prey types: long-nosed armadillo and white-lipped peccary. Literature data suggest that forest jaguars rely on the same mammal prey over their entire geographic range

A new map of the tiger shark (Galeocerdo cuvier) genetic population structure in the western Atlantic Ocean: Hypothesis of an equatorial convergence centre

The tiger shark (Galeocerdo cuvier) is a common widespread coastal–pelagic shark species whose population genetic structure has only recently been the object of genetic studies. In this study, the tiger's shark mitochondrial DNA control region was sequenced for a sample of 172 individuals from the western Atlantic and from Australia's east coast in the Pacific Ocean. The results show a moderate variation in genetic diversity (h = 0.615 ± 0.038, π = 0.00184 ± 0.00021) with a strong population structure between Atlantic areas (ΦST = 0.28141, P = 0.00001). The maternal lineage has high site fidelity, which paradoxically is coupled with connectivity across open ocean stretches to Fernando de Noronha Archipelago, which is identified as an important hotspot for this species. These results help with the understanding of what drives the displacement of this shark, at intra‐ and/or inter‐ocean basins levels, and can help inform the implementation of future conservation and management measures. We recommend that the conservation of genetic diversity should be maintained at a global level and its maintenance should be pursued diligently in all populations of tiger shark. As the Fernando de Noronha region in the western Atlantic appears to contain the largest global genetic diversity of the species, this area should be treated as a marine reserve or ecological refuge for the tiger shark.FCT IF/00253/2014info:eu-repo/semantics/publishedVersio